Complement System

1. Complement System The complement system consists of several plasma proteins that work together to opsonize microbes, to promote the recruitment of phagocytes to the site of infection, and, in some cases, to directly kill the microbes (Figure 1). The first step in activation of the complement system is recognition of molecules on microbial surfaces but not host cells, and this occurs in three ways, each referred to as a distinct pathway of complement activation. The classical pathway, so called because it was discovered first, uses a plasma protein called C1q to detect antibodies bound to the surface of a microbe or other structure (Figure 1A). Once C1q binds to the Fc portion of the antibodies, two associated serine proteases, called C1r and C1s, become active and initiate a proteolytic cascade involving other complement proteins. The classical pathway is one of the major effector mechanisms of the humoral arm of adaptive immune responses. Innate immune system soluble proteins called pentraxins, can also bind C1q and initiate the classical pathway. The alternative pathway, which was discovered later but is phylogenetically older than the classical pathway, is triggered when a complement protein called C3 directly recognizes certain microbial surface structures, such as bacterial LPS. C3 is also constitutively activated in solution at a low level and binds to cell surfaces, but it is then inhibited by regulatory molecules present on mammalian cells. Because microbes lack these regulatory proteins, the spontaneous activation can be amplified on microbial surfaces. Thus, this pathway can distinguish normal self from foreign microbes on the basis of the presence or absence of the regulatory proteins.